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Hematology. American Society of... Dec 2022Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the... (Review)
Review
Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.
Topics: Humans; Child; Dyskeratosis Congenita; Telomere; Germ-Line Mutation; Bone Marrow Failure Disorders; Anemia, Aplastic
PubMed: 36485133
DOI: 10.1182/hematology.2022000394 -
Oral Surgery, Oral Medicine, Oral... Jun 2018Oral potentially malignant disorders (OPMDs) are conditions that precede the onset of invasive cancers of the oral cavity. The term embraces precancerous lesions and... (Review)
Review
Oral potentially malignant disorders (OPMDs) are conditions that precede the onset of invasive cancers of the oral cavity. The term embraces precancerous lesions and conditions referred to in earlier World Health Organization (WHO) definitions. Leukoplakia is the most common OPMD; erythroplakia, although rare, is more serious. Several variants of leukoplakia are recognized, and clinical subtyping may help determine the prognosis to a limited extent. Biopsy is essential to confirm the provisional clinical diagnosis, and timely referral to a specialist is indicated. Certain OPMDs, such as oral submucous fibrosis, are encountered particularly in population groups from Asia with specific lifestyle habits. This review provides clinical descriptions of the wide range of potentially malignant disorders encountered in the oral cavity as a prelude to the topics discussed in this focus issue.
Topics: Biopsy; Cell Transformation, Neoplastic; Cheilitis; Diagnosis, Oral; Disease Progression; Dyskeratosis Congenita; Epidermolysis Bullosa; Erythroplasia; Graft vs Host Disease; Humans; Leukoplakia, Oral; Lichen Planus, Oral; Lupus Erythematosus, Discoid; Mouth Neoplasms; Oral Submucous Fibrosis; Precancerous Conditions; Risk Factors; Smoking
PubMed: 29673799
DOI: 10.1016/j.oooo.2018.03.011 -
Autopsy & Case Reports Sep 2020Dyskeratosis congenita (DC) is a genetic syndrome with progressive multisystem involvement classically characterized by the clinical triad of oral leukoplakia, nail...
Dyskeratosis congenita (DC) is a genetic syndrome with progressive multisystem involvement classically characterized by the clinical triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Frequent complications are bone marrow failure, increased rate of malignancy, lung and liver diseases. DC results from an anomalous progressive shortening of telomeres resulting in DNA replication problems inducing replicative senescence. We report a death due to DC in a 16-year-old male with bone marrow failure and multiple organ dysfunction. At autopsy, nail dystrophy and skin hypopigmentation were observed. Gross and microscopic examinations of the internal organs showed cardiac hypertrophy, multiple lung consolidations and prominent interstitial fibrosis, liver cirrhosis, and fibrosis. Multiple foci of extramedullary hematopoiesis were identified, including on the epidural surface of the dura, that is an infrequent location, mimicking a focal area of epidural hemorrhage. Only a few autopsy studies about DC are reported in the literature. Further research should be done to understand the pathophysiology of the disease and its complications.
PubMed: 33344307
DOI: 10.4322/acr.2020.203 -
Blood Aug 2022Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with ≥1 extrahematopoietic...
Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with ≥1 extrahematopoietic abnormalities. BM failure, which can involve ≥1 cell lineages, often presents in the pediatric age group. Furthermore, some children initially labeled as having idiopathic aplastic anemia or myelodysplasia represent cryptic cases of inherited BM failure. Significant advances in the genetics of these syndromes have been made, identifying more than 100 disease genes, giving insights into normal hematopoiesis and how it is disrupted in patients with BM failure. They have also provided important information on fundamental biological pathways, including DNA repair: Fanconi anemia (FA) genes; telomere maintenance: dyskeratosis congenita (DC) genes; and ribosome biogenesis: Shwachman-Diamond syndrome and Diamond-Blackfan anemia genes. In addition, because these disorders are usually associated with extrahematopoietic abnormalities and increased risk of cancer, they have provided insights into human development and cancer. In the clinic, genetic tests stemming from the recent advances facilitate diagnosis, especially when clinical features are insufficient to accurately classify a disorder. Hematopoietic stem cell transplantation using fludarabine-based protocols has significantly improved outcomes, particularly in patients with FA or DC. Management of some other complications, such as cancer, remains a challenge. Recent studies have suggested the possibility of new and potentially more efficacious therapies, including a renewed focus on hematopoietic gene therapy and drugs [transforming growth factor-β inhibitors for FA and PAPD5, a human poly(A) polymerase, inhibitors for DC] that target disease-specific defects.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Child; Dyskeratosis Congenita; Humans; Neoplasms; Pancytopenia
PubMed: 35605178
DOI: 10.1182/blood.2020006481 -
Genes Jun 2023Reticulate pigmentary disorders (RPDs) are a group of inherited and acquired skin conditions characterized by hyperpigmented and/or hypopigmented macules. Inherited RPDs... (Review)
Review
Reticulate pigmentary disorders (RPDs) are a group of inherited and acquired skin conditions characterized by hyperpigmented and/or hypopigmented macules. Inherited RPDs include dyschromatosis symmetrica hereditaria (DSH), dyschromatosis universalis hereditaria (DUH), reticulate acropigmentation of Kitamura (RAK), Dowling-Degos disease (DDD), dyskeratosis congenita (DKC), Naegeli-Franceschetti-Jadassohn syndrome (NFJS), dermatopathia pigmentosa reticularis (DPR), and X-linked reticulate pigmentary disorder. Although reticulate pattern of pigmentation is a common characteristic of this spectrum of disorders, the distribution of pigmentation varies among these disorders, and there may be clinical manifestations beyond pigmentation. DSH, DUH, and RAK are mostly reported in East Asian ethnicities. DDD is more common in Caucasians, although it is also reported in Asian countries. Other RPDs show no racial predilection. This article reviews the clinical, histological, and genetic variations of inherited RPDs.
Topics: Humans; Hyperpigmentation; Skin Diseases, Genetic
PubMed: 37372478
DOI: 10.3390/genes14061300 -
Orphanet Journal of Rare Diseases Oct 2020Revesz syndrome (RS) is an extremely rare variant of dyskeratosis congenita (DKC) with only anecdotal reports in the literature. (Review)
Review
BACKGROUND
Revesz syndrome (RS) is an extremely rare variant of dyskeratosis congenita (DKC) with only anecdotal reports in the literature.
METHODS
To further characterize the typical features and natural course of the disease, we screened the English literature and summarized the clinical and epidemiological features of previously published RS cases. In addition, we herein describe the first recorded patient in central Europe.
RESULTS
The literature review included 18 children. Clinical features are summarized, indicating a low prevalence of the classical DKC triad. All patients experienced early bone marrow failure, in most cases within the second year of life (median age 1.5 years; 95% CI 1.4-1.6). Retinopathy occurred typically between 6 and 18 months of age (median age 1.1 years; 95% CI 0.7-1.5). The incidence of seizures was low and was present in an estimated 20% of patients. The onset of seizures was exclusively during early childhood. The Kaplan-Meier estimate of survival was dismal (median survival 6.5 years; 95% CI 3.6-9.4), and none of the patients survived beyond the age of 12 years. Stem cell transplantation (SCT) was performed in eight children, and after a median of 22 months from SCT four of these patients were alive at the last follow up visit.
CONCLUSION
RS is a severe variant of DKC with early bone marrow failure and retinopathy in all patients. Survival is dismal, but stem cell transplantation may be performed successfully and might improve prognosis in the future.
Topics: Bone Diseases, Metabolic; Bone Marrow; Child; Child, Preschool; Dyskeratosis Congenita; Europe; Humans; Infant; Retina
PubMed: 33097095
DOI: 10.1186/s13023-020-01553-y -
Ophthalmology and Therapy Sep 2019Dyskeratosis congenita is a syndrome of bone marrow failure secondary to unstable telomeres. It is characterized by a range of mucocutaneous diseases. Due to premature...
Dyskeratosis congenita is a syndrome of bone marrow failure secondary to unstable telomeres. It is characterized by a range of mucocutaneous diseases. Due to premature telomere shortening, these patients have limbal stem cell deficiency leading to poor regeneration and maintenance of the cornea. Many of these patients will require hematopoietic stem cell transplant in their lifetime, which poses a significant risk for acute and chronic graft-versus-host disease with and without ocular manifestations. We advise against elective corneal refractive surgery in patients with dyskeratosis congenita due to the compounded and long-term risks of delayed healing secondary to limbal stem cell deficiency and ocular complications of graft-versus-host disease post-allogeneic hematopoietic stem cell transplant.
PubMed: 31313220
DOI: 10.1007/s40123-019-0200-z -
The New England Journal of Medicine Apr 2017
Topics: Blood Cell Count; Dyskeratosis Congenita; Humans; Leukoplakia; Male; Nail Diseases; Telomere
PubMed: 28402761
DOI: 10.1056/NEJMicm1613081